Studies using a variety of experimental approaches have established the existence of an inhibitory nervous system in mammalian airways which is neither adrenergic nor cholinergic. Because the neurotransmitter has not been identified, the system commonly is referred to as the nonadrenergic noncholinergic inhibitory system (NANCIS). The functional significance of this nervous system and its role in the pathophysiology of human airways disease presently are unknown. Also unknown is the nature of the chemical transmitter utilized by the system for postganglionic neurotransmission. Further, aside from a lack of sensitivity to a variety of pharmacologic antagonists, relatively little is known about the system's basic pharmacologic characteristics. Previous studies in our laboratory have established the functional presence of the lung NANCIS in the intact cat. Experiments in vitro have since confirmed and extended these findings. The studies outlined in the current proposal will utilize both in vivo and isolated tissue techniques to: (1) assess the functional significance of the lung NANCIS by detemrining whether the system can be activated by phsiologically relevant stimuli and whether it plays a role in controlling airways responsiveness to bronchoconstrictive stimuli, (2) develop an in vivo model of the lung NANCIS in a nonhuman primate; (3) demonstrate release and characterize the nature of the NANCIS neurotransmitter in isolated cat airway smooth muscle; and (4) characterize the lung NANCIS with regard to its modulation by other neurotransmitters or hormones and identify possible mechanisms through which the system produces inhibitory effects on airways smooth muscle. By demonstrating the functional significance of the lung NANCIS, this research could provide new insight into the physiologic mechanisms regulating airway caliber and the pathogenic mechanisms underlying airways hyperreactivity. Additionally, the pharmcologic information derived from these studies could provide a rationale for the synthesis of more effective therapeutic agents for the treatment of hyperreactive airways tissue.